Crystal form of lenvatinib methanesulfonate salt and preparation method thereof

ABSTRACT

The present disclosure relates to a novel crystalline form of lenvatinib mesylate and the preparation method thereof. The novel crystalline form of mesylate of the present disclosure can be used for treating invasive and differentiated thyroid cancer. The novel crystalline form of mesylate of the present disclosure has good solubility, stability, and remarkable purification effect in process. The preparation method of this novel crystalline form is simple, low cost, and has an important value for future optimization and development of the drug.

TECHNICAL FIELD

The present disclosure relates to the field of chemical pharmaceuticals,particularly relates to a novel crystalline form of lenvatinib mesylateand process of preparation and uses thereof.

BACKGROUND

Lenvatinib is an oral multiple receptor tyrosine kinase (RTK) inhibitorsfor treating invasive and differentiated thyroid cancer developed byEisai Co., and was approved on Feb. 13, 2015 by FDA. Lenvatinib mesylateis used in the approved drug. The chemical name of the drug is4-{3-Chloro-4-[(cyclopropylcarbamoyl)amino]phenoxy}-7-methoxy-6-quinolinecarboxamide,and the structure is shown as formula I:

Since different crystalline forms of the same compound are different insolubility and stability, absorption and bioavailability, andtherapeutic effect will be affected. Thus, a comprehensive andsystematic polymorph and salts screening to select the most suitablecrystalline form or salt form for development cannot be ignored.

CN1890220A disclosed crystalline Form A, Form B, Form C, Form F and FormI of lenvatinib mesylate. Form α and Form β of lenvatinibethanesulfonate was also disclosed. The inventors of the presentdisclosure surprisingly find novel crystalline Form M of lenvatinibmesylate. Form M is different from any form disclosed in CN1890220A. Inaddition, Form M of lenvatinib mesylate of the present disclosure hasgood stability and remarkable purification effect in process. Theprocess of novel crystalline forms is simple, low cost, and has animportant value for future optimization and development of the drug.

SUMMARY OF THE DISCLOSURE

One objective of the present disclosure is to provide a novelcrystalline form of lenvatinib mesylate, designated as Form M, which canimprove solubility of lenvatinib mesylate.

Lenvatinib Mesylate is Compound (I) Mesylate

The crystalline Form M of lenvatinib mesylate of the present disclosure,its X-ray powder diffraction pattern shows at least three characteristicpeaks at 2theta values of 11.3°±0.2°, 6.1°±0.2°, 15.2°±0.2°, 17.9°±0.2°,23.5°±0.2°, 21.8°±0.2°, 7.9°±0.2°, 10.1°±0.2° and 22.8°±0.2°.

Preferably, one of said three characteristic peaks is at 2theta valuesof 11.3°±0.2°.

More preferably, the other two of said three characteristic peaks are at2theta values of 6.1°±0.2° and 15.2°±0.2°.

As a preferred example of the present disclosure: crystalline Form M oflenvatinib mesylate of the present disclosure, its X-ray powderdiffraction pattern shows at least six characteristic peaks at 2thetavalues of 11.3°±0.2°, 6.1°±0.2°, 15.2°±0.2°, 17.9°±0.2°, 23.5°±0.2°,21.8°±0.2°, 7.9°±0.2°, 10.1°±0.2° and 22.8°±0.2°. Preferably, three ofthe six characteristic peaks are at 2theta values of 11.3°±0.2°,6.1°±0.2° and 15.2°±0.2°. More preferably, the other three of the sixcharacteristic peaks are at 2theta values of 17.9°±0.2°, 23.5°±0.2° and21.8°±0.2°.

According to a specific and preferred aspect of the present disclosure,the X-ray powder diffraction pattern of the crystalline Form M oflenvatinib mesylate shows characteristic peaks at 2theta values of11.3°±0.2°, 6.1°±0.2°, 15.2°±0.2°, 17.9°±0.2°, 23.5°±0.2°, 21.8°±0.2°,7.9°±0.2°, 10.1°±0.2° and 22.8°±0.2°.

According to a specific example, the X-ray powder diffraction pattern ofthe crystalline Form M of lenvatinib mesylate of the disclosure issubstantially as shown in FIG. 1.

According to a specific example, the differential scanning calorimetryanalysis thermogram (DSC) of the crystalline Form M of lenvatinibmesylate of the disclosure is substantially as shown in FIG. 2.

According to a specific example, the thermal gravimetric analysis (TGA)thermogram of crystalline Form M of lenvatinib mesylate of thedisclosure is substantially as shown in FIG. 3.

Another objective of the present disclosure is to provide a process forpreparing crystalline Form M of lenvatinib mesylate, comprising addingcompound (I) and methanesulfonic acid into an appropriate crystallizingsolvent, stirring to get Form M.

Furthermore, the appropriate crystallizing solvent comprises single ormixed solvents selected from water, alcohols, ketones, nitriles, cyclicethers, and aliphatic hydrocarbons.

Furthermore, the appropriate crystallizing solvents are nitriles orsolvents containing nitriless, specifically, the crystallizing solventis acetonitrile.

According to a specific aspect of the present disclosure, the process ofcrystalline Form M of lenvatinib mesylate comprises: adding lenvatinibpowder in acetonitrile to obtain a suspension, and addingmethanesulfonic acid dropwise into the suspension, then stirring at roomtemperature and centrifuging to give a solid, drying the solid overnightto get Form M. Furthermore, the stirring time is preferably over 12hours, and more preferably is over 20 hours. The drying condition ispreferably at room temperature.

Another objective of the present disclosure is to provide apharmaceutical composition comprising an effective dose of crystallineForm M of lenvatinib mesylate and pharmaceutical acceptable excipients.

Furthermore, the crystalline Form M of lenvatinib mesylate of thepharmaceutical composition of the present disclosure can be used forpreparing drugs treating cancers, especially preparing pharmaceuticalformulations treating thyroid cancer.

The present disclosure provides crystalline Form M of lenvatinibmesylate for preparing a drug for treating cancers, especially for theuse of preparing drugs treating thyroid cancer.

The present disclosure has the following advantages:

Comparing with crystalline forms of lenvatinib mesylate in prior art,the crystalline Form M of lenvatinib mesylate has improved solubility.In addition, the crystalline Form M of lenvatinib mesylate of thepresent disclosure has good stability (Crystal transformation duringdrug storage and development can be avoided, so the change ofbioavailability and efficacy can be avoided), good crystal morphology,and remarkable purification effect in process. The preparation method ofnovel crystalline forms is simple, low cost, and has an important valuefor future optimization and development of the drug.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows an XRPD pattern of crystalline Form M of lenvatinibmesylate;

FIG. 2 shows a DSC thermogram of crystalline Form M of lenvatinibmesylate;

FIG. 3 shows a TGA thermogram of crystalline Form M of lenvatinibmesylate.

FIG. 4 shows a ¹HNMR spectrum of crystalline Form M of lenvatinibmesylate.

FIG. 5 shows an Infrared spectrum of crystalline Form M of lenvatinibmesylate.

FIG. 6 shows a polarized light microscopy image of crystalline Form M oflenvatinib mesylate.

FIG. 7a ˜7 c show XRPD patterns overlay of crystalline Form M oflenvatinib mesylate before and after stored in the following conditionsfor 7 days: a) sealed in aluminum plastic bags at 25° C./60% RH; b)sealed in aluminum plastic bags at 40° C./75% RH; c) sealed in aluminumplastic bags at 60° C./75% RH.

DETAILED DESCRIPTION

The present disclosure will be further explained by the specificexamples, but the disclosure is not intended to limit the scope of thepresent disclosure. The skilled in the art can make improvements to theprocess of preparation and the used instruments within the scope of theclaims, and those improvements should be considered as falling into thescope of the present disclosure. Therefore, the scope of the presentdisclosure patent should be defined by the claims.

In the following examples, the experimental methods were implementedgenerally in accordance with conventional conditions or conditionsrecommended by the manufacturers.

The abbreviations used in the disclosure are explained as follows:

-   -   XRPD: X-ray Powder Diffraction    -   DSC: Differential Scanning Calorimetry    -   TGA: Thermal Gravimetric Analysis    -   ¹H NMR: ¹H Nuclear Magnetic Resonance

X-ray powder diffraction pattern of the present disclosure is collectedby a Panalytical Empyrean X-ray powder diffractometer. The parameters ofthe X-ray powder diffraction method of the present disclosure are asfollows:

-   -   X-ray Reflection: Cu, Kα    -   Kα1 (Å): 1.540598; Kα2 (Å): 1.544426    -   Kα2/Kα1 intensity ratio: 0.50    -   Voltage: 45 (kV)    -   Current: 40 (mA)    -   Scan range: from 3.0 degree to 40.0 degree

Differential scanning calorimetry (DSC) data in the present disclosureis collected by a TA Q2000. The parameters of the differential scanningcalorimetry (DSC) method of the present disclosure are as follow:

-   -   Heating rate: 10° C./min    -   Purge gas: nitrogen.

Thermal gravimetric analysis (TGA) data in the present disclosure iscollected by a TA Q5000. The parameters of the thermal gravimetricanalysis (TGA) method of the present disclosure were as follow:

-   -   Heating rate: 10° C./min;    -   Purge gas: nitrogen.

Polarized light microscopy (PLM): Polarized light microscopy image iscollected by an Axio Lab. Al upright microscope at room temperature.

EXAMPLE 1

Process for preparing crystalline Form M of lenvatinib mesylate:

50.2 mg of lenvatinib was added into 4.0 mL of acetonitrile to obtain asuspension, and 10 μL of methanesulfonic acid (mass concentration:99.5%) was dropwise added to the suspension, then it was stirred at roomtemperature for 24 hours and centrifuged to obtain solid. The solid wasdried at 25° C. overnight, and the obtained solid was identified ascrystalline Form M of lenvatinib mesylate.

The XRPD pattern of Form M of the example is displayed in FIG. 1, the ¹HNMR spectrum is displayed in FIG. 4. The IR spectrum is displayed inFIG. 5. Among them:

The XRPD data is listed in Table 1.

TABLE 1 2 theta (°) d spacing Intensity % 6.14 14.40 75.59 7.85 11.2633.94 10.07 8.78 33.61 11.34 7.81 100.00 12.55 7.05 11.76 15.19 5.8353.50 16.99 5.22 32.29 17.90 4.96 45.13 18.54 4.78 12.19 19.38 4.58 7.4920.13 4.41 10.55 21.83 4.07 41.20 22.80 3.90 32.45 23.46 3.79 43.9223.80 3.74 43.36 24.72 3.60 20.03 26.28 3.39 30.01 27.26 3.27 10.0628.50 3.13 11.88 29.15 3.06 7.19 30.99 2.89 2.58 33.25 2.69 3.62

¹H NMR data is shown in the following:

¹H-NMR(400 MHz, DMSO-d₆) δ 8.91 (d, J=60 Hz, 1H), 8.73 (s, 1H), 8.36 (d,J=9.1 Hz, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.85 (s, 1H), 7.56-7.64 (m,2H), 7.34 (dd, J1=9.1 Hz, J2=2.7 Hz, 1H), 7.24 (d, J=2.9 Hz, 1H),6.86(d, J=5.4 Hz, 1H), 4.09 (s, 3H), 2.56-2.63 (m, 1H), 2.31 (s, 3H),0.65-0.72 (m, 2H), 0.41-0.47 (m, 2H).

IR data is shown as follows:

Absorption peaks (cm⁻¹): 426.17, 535.72, 552.31, 641.51, 674.45, 750.73,772.99, 842.47, 909.84, 931.62, 983.18, 1039.43, 1054.78, 1091.43,1155.96, 1190.77, 1238.18, 1260.41, 1293.34, 1325.61, 1353.10, 1400.53,1457.75, 1529.56, 1616.33, 1669.59, 1692.73, 3119.43, 3249.08, 3415.02,3469.14.

The DSC thermogram of Form M is displayed in FIG. 2, the TGA thermogramis displayed in FIG. 3. The PLM image of Form M is displayed in FIG. 6,indicating the crystalline Form M has good crystal morphology anduniform particle size distribution.

EXAMPLE 2

Process for preparing crystalline Form M of lenvatinib mesylate:

105.3 mg of lenvatinib powder was added into 12.0 mL of acetonitrile toobtain a suspension, and 30 μL of methanesulfonic acid (massconcentration: 99.5%) was dropwise added to the suspension, then it wasstirred at room temperature for 24 hours and centrifuged to obtainsolid. The solid was dried at 25° C. overnight, and the obtained solidwas identified as crystalline Form M of lenvatinib mesylate.

The X-ray powder diffraction data of Form M of the example is listed inTable 2.

TABLE 2 2 theta (°) d spacing Intensity % 6.12 14.45 76.19 7.77 11.3828.62 10.07 8.78 21.83 11.34 7.81 100.00 12.56 7.05 8.67 15.18 5.8446.69 17.00 5.22 28.50 17.91 4.95 47.27 18.61 4.77 17.60 20.17 4.4014.60 21.78 4.08 50.93 22.71 3.92 36.31 23.44 3.80 54.89 23.83 3.7350.46 24.74 3.60 27.04 26.30 3.39 37.22 28.46 3.14 17.39 33.09 2.71 5.5335.65 2.52 2.98

EXAMPLE 3

Solubility comparison between crystalline Form M of lenvatinib mesylateof the present disclosure and anhydrate Form C in patent CN1890220A:

Crystalline Form M of lenvatinib mesylate prepared in example 1 andanhydrate Form C in CN1890220A were prepared into saturated solution inpH 1.8 SGF (Simulated gastric fluid), pH 5.0 FeSSIF (Fed state simulatedintestinal fluid), FassIF (Fasted state simulated intestinal fluid) andhigh purity water. Concentrations in the saturated solutions weredetermined after 24 hours by HPLC. The result is displayed in Table 3

TABLE 3 Time High purity point SGF FaSSIF FeSSIF water (h) Form C Form MForm C Form M Form C Form M Form C Form M Solubility 24 0.64 0.69 0.00150.024 0.0003 0.0004 1.0 1.6 (mg/mL)

The result suggests that crystalline Form M of lenvatinib mesylate ofthe present disclosure has higher solubility in comparison with Form Cin patent CN1890220A. Specially, Form M has evident advantage insolubility in FaSSIF and high purity water in comparison with Form C.

EXAMPLE 4

Stability assessment of Form M of lenvatinib mesylate of the presentdisclosure:

Three samples of crystalline Form M of lenvatinib mesylate were storedunder the following conditions: a) sealed in aluminum plastic bags at25° C./60% RH; b) sealed in aluminum plastic bags at 40° C./75% RH; c)sealed in aluminum plastic bags at 60° C./75% RH. The samples weretested by XRPD before and after stored for 7 days. The XRPD patternsbefore and after storage are compared, and the results are displayed inFIG. 7a ˜7 c. As shown in FIG. 7a ˜7 c, Form M of the disclosureremained unchanged before and after storage, and the characteristicpeaks maintain highly consistent. Thus indicates that the crystallineForm M of lenvatinib mesylate has excellent stability.

The invention claimed is:
 1. A crystalline Form M of compound (I)mesylate, wherein the X-ray powder diffraction pattern shows at leastthree characteristic peaks at 2theta values of 11.4°±0.2°, 6.1°±0.2°,15.1°±0.2°, 12.5°±0.2°, 23.8°±0.2°, 21.8°±0.2°, 7.9°±0.2° and 20.2±0.2°.


2. The crystalline Form M of compound (I) mesylate according to claim 1,wherein the three characteristic peaks are at 2theta values of6.1°±0.2°, 7.9°±0.2° and 21.8°±0.2°.
 3. The crystalline Form M ofcompound (I) mesylate according to claim 2, wherein a at leastadditional one characteristic peak is at 2theta values of 11.4°±0.2°,15.1°±0.2° or 12.5°±0.2°.
 4. The crystalline Form M of compound (I)mesylate according to claim 3, wherein the X-ray powder diffractionpattern shows characteristic peaks at 2theta values of 11.4°±0.2°,15.1°±0.2° and 12.5°±0.2°.
 5. The crystalline Form M of compound (I)mesylate according to claim 2, wherein the X-ray powder diffractionpattern shows at least one additional characteristic peak at 2thetavalues of 23.8°±0.2° and 20.2°±0.2°.
 6. The crystalline Form M ofcompound (I) mesylate according to claim 5, wherein the X-ray powderdiffraction pattern shows characteristic peaks are at 2theta values of23.8°±0.2° and 20.2°±0.2°.
 7. The crystalline Form M of compound (I)mesylate according to claim 1, wherein an X-ray powder diffractionpattern is substantially as shown in FIG.
 1. 8. The crystalline Form Mof compound (I) mesylate according to claim 1, wherein Fourier TransformInfrared (FT-IR) spectrometer has the following absorption bandsexpressed in reciprocal wave numbers: 535.72±1cm⁻¹ and 1400.53±1cm^(−1.)
 9. The crystalline Form M of compound (I) mesylate according toclaim 1, wherein Fourier Transform Infrared (FT-IR) spectrometer has thefollowing absorption bands expressed in reciprocal wave numbers:1190.77±1cm⁻¹ and 1692.73±1cm⁻¹.